DNA Methylation Mediates the Transcription of STAT4 to Regulate KISS1 During Follicular Development

Danxia Chen; Ming Fang; Enyuan Huang; Hongyan Quan; Liuhong Zhang; Yingting He; Xiaofeng Zhou; Bin Ma; Xiaolong Yuan; Jiaqi Li

doi:10.3390/cells14070523

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DNA Methylation Mediates the Transcription of STAT4 to Regulate KISS1 During Follicular Development

Journal article

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Peer reviewed

DNA Methylation Mediates the Transcription of STAT4 to Regulate KISS1 During Follicular Development

Danxia Chen, Ming Fang, Enyuan Huang, Hongyan Quan, Liuhong Zhang, Yingting He, Xiaofeng Zhou, Bin Ma, Xiaolong Yuan and Jiaqi Li

Cells (Basel, Switzerland), Vol.14(7), 523

2025

DOI: https://doi.org/10.3390/cells14070523

PMID: 40214477

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Abstract

Animals

Apoptosis - genetics

Cell Proliferation - genetics

DNA Methylation - genetics

Female

Granulosa Cells - cytology

Granulosa Cells - metabolism

Kisspeptins - genetics

Kisspeptins - metabolism

Mice

Ovarian Follicle - growth & development

Ovarian Follicle - metabolism

Promoter Regions, Genetic - genetics

STAT4 Transcription Factor - genetics

STAT4 Transcription Factor - metabolism

Swine

Transcription, Genetic

Maturation of follicles is the primary condition for the initiation of puberty, and excessive apoptosis of granulosa cells (GCs) will hinder the normal development of follicles in pigs. Signal Transducer and Activator of Transcription 4 (STAT4) plays an important role in cell proliferation and apoptosis. However, the mechanism of DNA methylation regulating STAT4 transcription and affecting follicle development in pigs remains unclear. To resolve this problem, we constructed a STAT4 overexpression vector and interference fragment to explore the effects of STAT4 on GC function and investigate the effects of changes in methylation status of the STAT4 promoter region on cell function and kisspeptin-1 (KISS1) expression, as well as the STAT4 effects on the development of the follicles of pigs and mice in vitro. We found that the expression of STAT4 decreased, while DNA methylation of the STAT4 promoter region increased with the growth of the follicles. After overexpression of STAT4, the apoptosis of GCs was increased but the proliferation, cell cycle and estrogen secretion of GCs were inhibited. When GCs were treated with DNA methyltransferase inhibitor (5-Aza-CdR), the methylation of the STAT4 promoter region decreased, resulting in a significant increase in the expression of STAT4. Consequently, the expression of KISS1 was inhibited. At the same time, the expressions of genes related to cell proliferation, cell cycle and estrogen secretion signaling pathways decreased, while the expressions of genes related to the apoptosis signaling pathway increased. After infection with the STAT4 lentiviral vector (LV-STAT4) in follicles of mice, the expression of STAT4 in ovaries of mice significantly increased, and the expression of KISS1 was significantly decreased. The capillaries on the surface of follicles were constricted, the age of puberty onset in mice was delayed while the levels of GnRH, LH, FSH and E2 in serum were decreased. In conclusion, we found that reduced methylation status of the STAT4 promoter region promoted the transcription of STAT4 and then inhibited the expression of KISS1, as well as promoted the apoptosis of GCs and ultimately inhibited the normal development of follicles in mammals.

Details

Title: DNA Methylation Mediates the Transcription of STAT4 to Regulate KISS1 During Follicular Development
Authors/Creators: Danxia Chen - South China Agricultural University
Ming Fang - South China Agricultural University
Enyuan Huang - South China Agricultural University
Hongyan Quan - South China Agricultural University
Liuhong Zhang - South China Agricultural University
Yingting He - South China Agricultural University
Xiaofeng Zhou - South China Agricultural University
Bin Ma - Murdoch University, School of Medical, Molecular and Forensic Sciences
Xiaolong Yuan - South China Agricultural University
Jiaqi Li - South China Agricultural University
Publication Details: Cells (Basel, Switzerland), Vol.14(7), 523
Publisher: MDPI
Number of pages: 19
Grant note: CARS-35 / Supported by the earmarked fund for China Agriculture Research System 32072694 / National Natural Science Foundation of China 2022-4408X1-43010402-0019 / Breed Industry Innovation Park of Guangdong Xiaoerhua Pig
Identifiers: 991005765132007891
Murdoch Affiliation: Centre for Healthy Ageing
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.81 Reproductive Biology; 1.81.1408 Fertility Preservation
Web Of Science research areas: Cell Biology
ESI research areas: Biology & Biochemistry